GRANT=6446814;P01AG The presence of a naturally occurring substance(s), secreted from the gut, stimulated by ingestion of food, that lowers plasma glucose levels was postulated over 90 years ago. In the early 1930's the term "incretin" was coined for this hypothesized substance. Two substance have been identified which fulfill all the roles postulated for incretins: glucose-dependent-insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). Both peptides are insulinotropic and the stimulatory is directly proportional to the degree of hyperglycemia. GLP-1 is several fold more potent than GIP. Only GLP-1 is insulinotropic in type 2 diabetic subjects when administered intravenously. Its half-life, however, is very short (2 minutes). An agonist of GLP-1, Exendin-4 (EX-4), present in the saliva of Gila monsters, has 10 fold the potency of GLP-1 with at least 240 fold longer half-life. Ex-4 is also insulinotropic in type 2 diabetes. The purpose of this proposal is to test the efficacy of subcutaneously administered GLP-1 or Ex-4 to type 2 diabetic subjects and to examine the mechanism whereby improvements in glucose homeostasis are obtained. Specifically, the hypotheses are: a. Trophic hormone releasing factor administration (GLP and Ex-4) will correct the endocrinopathy of aging (low insulin) in a safe and quantifiable fashion. b. Corrected trophic factor levels (GLP and EX-4) result in improved tissue structure and function. C. The restoration of tissue trophism to normal is mechanistically linked to fundamental changes in tissue actions, including effects on fuel utilization brought on by insulin and incretins themselves, such as translocation of GLUT-4. It is anticipated that these peptides will prove to be very efficacious in the treatment of type 2 diabetes and will be superior to the usual oral hypoglycemic agents because its effects will not erode with prolonged use and the occurrence of hypoglycemic episodes will be nearly or totally eliminated.